This Project builds on recent observations from the EAS and elsewhere indicating that both stress and pain are Important risk factors for cognitive decline and dementia. Although pain contributes to stress and stress to pain, we recognize that these exposures are distinct. We propose to assess them together because they are associated at a behavioral level, have overlapping effects on the hypothalamic-pituitary-adrenal (HPA) axis and on cognitive function. In addtion they share similar psychosocial and genetic moderators, and present measurement challenges that can be addressed using similar intensive measurement strategies. The overall goal of this project is to examine the Influence of experiential (e.g., daily and chronic pain, daily stressors and life events) and biological factors (e.g., glucocorticoid dysregulation) on cognitive decline and dementia risk in the elderly. This Project will use annual assessments as well as an intensive measurement burst to provide precise measurements ofthe experience of pain and stress as well as their physiologic consequences. The measurement burst consists of an 8-day telephone diary assessing pain, daily stressors, mood, and activity limitations; participants also provide multiple salivary samples per day over 4 days for analysis of diurnal Cortisol profiles to assess the HPA axis dysfunction. We will assess the Influence of pain, stress and glucocorticoids on measures of microvascular disease (retinal photography and reactivity to carbon dioxide as assessed by transcranial doppler) from Project 2. With Project 3, we will access the influence of pain, stress, and glucocorticoids on locomotion. Participants will complete in-lab annual cognitive assessment of episodic memory, working memory, executive function and processing speed because deficits In these domains have been linked to pain and stress in older adults. This design will allow us to determine how daily pain and stress as well as related processes (e.g., blunted morning Cortisol response, heightened emotional reactivity to daily stress) influence neuro-imaging as well as cognitive decline and dementia risk. We will also examine the influence of selected candidate genes, personality (e.g. neuroticism) and psychosocial factors (e.g., social support) on these pathways. RELEVANCE (See instructions): Pain and stress are common in late adult life and powerfully Influence brain structure and function. Yet they remain understudied as risk factors for cognitive decline. This study will yield insights into early behavioral and biological indicators of dementia, improving preclinical detection of disease and facilitating the development of novel preventive strategies.